This invention concerns a method for producing a drug system for delivering a drug or other agent for the treatment of a condition in a controlled release manner.
Most known xe2x80x98controlled-releasexe2x80x99 drug systems are constant slow-release mechanisms (U.S. Pat. No. 4,145,410). These systems do not react to any inherent substances in the body to release the drug appropriately in response to that substance, ie. there is no feedback mechanism. Feedback mechanisms have been suggested to be of interest in vivo to maintain general homeostasis.
U.S. Pat. No. 4,348,387 discloses a feedback controlled insulin delivery system wherein glucose-insulin conjugates are displaced from glucose binding sites on a binding molecule by free glucose. The conjugated insulin retains its biological activity once released. However, it is not known whether other agents or drugs can be so conjugated or whether such a conjugated form of any drug or other agent would be effective.
The present invention provides a delivery system for the controlled release of an unconjugated drug or other agent for possible use in vivo.
According to the present invention there is provided a method for producing a system for delivering a drug for the treatment of a condition, comprising immobilising a drug or other agent in a bio-compatible matrix containing at least one receptor for a physiological substance which will be in the environment of the matrix when administered, said receptor being anchored within the matrix but remaining biologically active being activated in response to the levels of said physiological substance to effect a conformational change in the matrix allowing mobilisation and release of the drug only into the environment.
The agent may comprise a naturally occurring biological agent, for example, a hormone, which may, of course, be insulin, as in U.S. Pat. No. 4,348,387, but now in unconjugated form. Because there is now no need for conjugation, other hormones or drugs which it may not be possible to conjugate or which will not work in the system of U.S. Pat. No. 4,348,387 even if they can be conjugated, or which may be physiologically ineffective or less effective or even harmful when conjugated, may be used according to the invention.
The receptor may be a binding macromolecule, for example, a lectin, which may be concanavalin-A, a lectin produced from the jack bean. Because the binding macromolecule is anchored within the matrix, it is not necessary to enclose the system within a semi-permeable membrane, tube or other device, as is the case in the system of U.S. Pat. No. 4,348,387. Such a method of restraining the drug system may alter the kinetics of the drug releasing mechanism and result in reduced sensitivity. Additionally, should the retaining device disintegrate, toxic lectin molecules would be released into the general circulation. The present invention provides a system which overcomes these disadvantages and allows lectins to be used more safely.
The receptor may reversibly bind the physiological substance, which may be a carbohydrate, preferably glucose, fructose or mannose or a carbohydate polymer containing glucose moieties, such as branched starches, dextrans, mannans and levans or synthetic carbohydrates, for example, ficoll-400, a synthetic polysucrose.
Insulin, or any other agent or drug, may be immobilised in the matrix when terminal glucose molecules on dextran bind to concanavalin-A to form a gel.
Concanavalin-A molecules are anchored within the matrix by covalent bonding to the polymeric chains of dextran without-forming insoluble aggregates. Such a system allows maintenance of the structure and function of the matrix. The concanavalin-A may be covalently bonded to the dextran in any conventional manner, for example;
via the sodium iodate oxidation to Schiff bases of vicinial OH groups on dextran, followed by reduction and purification by precipitation;
via azide bonding to linear polyacrylamide hydrazide;
via glutaraldehyde bonding to linear polyacrylamide.
The conformational change in the matrfix may be brought about by the displacement of terminal dextran-glucose molecules from the receptor by free glucose in the physiological environment which may of course be blood or other tissue fluid or fluid in the lumen of the digestive tract.
The conformational change may be an ungelling of the matrix allowing mobilisation and release of the insulin or other agent or drug.
The drug system may be specific to monosaccharides including xcex1D-mannose, xcex1-D-glucose and xcex1- and xcex2-fructose and disaccharides including maltose and di-glucose with an xcex1-linkage.
The drug system may-not be affected by changes in pH from 4.0 to 8.0 nor by changes in the Mn++ or Ca++ ion concentration of the surrounding environment.
The drug system may be presented to a patient in vivo in a number of ways, for example, orally using oral hypoglycaemic drugs (insulin may not be used orally as it would not be absorbed in an active form) or by a subcutaneous implant, for example.